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Introduction: Social disconnection and deaths by suicide among older adults are both important public health concerns, particularly in the context of ageing populations. The association between death ideation and behaviours, and social disconnection is well established and both functional and structural social relationships have been identified as predictive of suicide-related thoughts and behaviours. The "Wish to Die" (WTD) involves thoughts of or wishes for one's own death or that one would be better off dead is a commonly used indicator to capture death ideation. It has been shown to be as predictive as active ideation of future suicide attempt. Methods: Data were from a large cohort of community-dwelling older adults aged 50+, The Irish Longitudinal Study on Ageing (TILDA). Cross-sectional analyses of the association between numerous markers of social disconnection (loneliness, social isolation, living alone, marital status, social participation, volunteering, and attending religious service) and WTD were conducted. Results: Multiple markers of social disconnection were associated with a "wish to die". However, loneliness was the strongest risk factor while attendance of religious services was an important protective behaviour. Discussion: There is a strong association between social disconnection and a WTD among older adults. There is also a strong association between depression and a WTD, while attending religious services or similarly prosocial settings may protect older adults from experiencing negative thoughts about dying.
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Vida Independiente , Soledad , Aislamiento Social , Humanos , Anciano , Masculino , Femenino , Estudios Transversales , Persona de Mediana Edad , Estudios Longitudinales , Irlanda , Soledad/psicología , Aislamiento Social/psicología , Factores de Riesgo , Ideación Suicida , Anciano de 80 o más Años , Participación SocialRESUMEN
Background: An integrated haemodynamic response during standing may serve as an integrative marker of neuro-cardiovascular function. Individual components of both heart rate (HR) and blood pressure (BP) responses to active stand (AS) have been linked with cardiovascular disease (CVD) and mortality. We assessed longitudinal associations between entire HR/BP response curves during AS, incident CVD and mortality over 12 years. Methods: Beat-to-beat measurements of dynamic HR/BP responses to AS were conducted in 4,336 individuals (61.5±8.2 years; 53.7% female). Functional Principal Components Analysis was applied to HR/BP response curves and their association with CVD and mortality assessed. We hypothesised that integrating BP/HR information from the entire haemodynamic response curve may uncover novel associations with both CVD and mortality. Results: Higher systolic BP (SBP) before AS and blunted recovery of SBP during AS was associated with all-cause mortality over 12-years (Hazard Ratio [HR]: 1.14; 1.04, 1.26; p=0.007). Higher baseline/peak HR and lower HR from 30 seconds post stand onwards were associated with lower mortality due to circulatory causes (HR: 0.78; 0.64, 0.95; p = 0.013). Higher HR throughout AS was associated with mortality from other causes (HR: 1.48; 1.22, 1.80; p<0.001). Findings persisted on robust covariate adjustment. Conclusions: We observed distinct relationships between HR/BP responses to AS and 12-year incident CVD and mortality. Integrating the entire haemodynamic response may reveal more nuanced relationships between HR/BP responses to AS, CVD and mortality - serving as an integrative marker of neuro-cardiovascular health in midlife and beyond.
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Medication-use evaluations are meant to ensure that medication-use processes are consistent with prevailing standards of care, assure optimal use of therapy, and reduce the risk of medication-related problems. Reversal agents for direct oral anticoagulants are a worthy focus for medication-use evaluations for reasons of efficacy, safety, and cost. A multidisciplinary team of experts developed 2 medication-use evaluation templates illustrating the application of professional society guidelines to the appropriate use of andexanet alfa.
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Improving access to primary care physicians' services may help reduce hospitalizations due to Ambulatory Care Sensitive Conditions (ACSCs). Ontario, Canada's most populous province, introduced blended payment models for primary care physicians in the early- to mid-2000s to increase access to primary care, preventive care, and better chronic disease management. We study the impact of payment models on avoidable hospitalizations due to two incentivized ACSCs (diabetes and congestive heart failure) and two non-incentivized ACSCs (angina and asthma). The data for our study came from health administrative data on practicing primary care physicians in Ontario between 2006 and 2015. We employ a two-stage estimation strategy on a balanced panel of 3710 primary care physicians (1158 blended-fee-for-service (FFS), 1388 blended-capitation models, and 1164 interprofessional team-based practices). First, we account for the differences in physician practices using a generalized propensity score based on a multinomial logit regression model, corresponding to three primary care payment models. Second, we use fractional regression models to estimate the average treatment effects on the treated outcome (i.e., avoidable hospitalizations). The capitation-based model sometimes increases avoidable hospitalizations due to angina (by 7 per 100,000 patients) and congestive heart failure (40 per 100,000) relative to the blended-FFS-based model. Switching capitation physicians into interprofessional teams mitigates this effect, reducing avoidable hospitalizations from congestive heart failure by 30 per 100,000 patients and suggesting better access to primary care and chronic disease management in team-based practices.
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Planes de Aranceles por Servicios , Insuficiencia Cardíaca , Hospitalización , Atención Primaria de Salud , Humanos , Ontario , Atención Primaria de Salud/economía , Hospitalización/economía , Hospitalización/estadística & datos numéricos , Masculino , Femenino , Insuficiencia Cardíaca/terapia , Insuficiencia Cardíaca/economía , Persona de Mediana Edad , Planes de Aranceles por Servicios/economía , Anciano , Diabetes Mellitus/terapia , Capitación , Asma/terapia , Asma/economía , Médicos de Atención Primaria/economía , Angina de Pecho/terapia , Angina de Pecho/economíaRESUMEN
Purpose: To examine if changes in hemodynamic measures during an orthostatic challenge were associated with progression of age-related macular degeneration (AMD) over a 4-year period in The Irish Longitudinal Study on Ageing. Methods: Participants with AMD who underwent an active stand (AS) test at wave 1 (2009/2010) and retinal photographs at both wave 1 and wave 3 (2014/2015) were included (N = 159: 121 with no AMD progression and 38 with progression). Beat-to-beat hemodynamic data were non-invasively collected using a Finometer MIDI device during the AS at wave 1, recording systolic blood pressure (sBP), diastolic blood pressure (dBP), mean arterial pressure (MAP), and heart rate. Cardiac output, stroke volume, and total peripheral resistance (TPR) were derived from these measures. Baseline characteristics were compared between groups with and without AMD progression. Mixed-effects linear regression models were used to assess the association between changes in hemodynamic parameters during the AS and AMD progression, controlling for known AMD-associated risk factors. Results: At baseline, increasing age and lower dBP were significantly associated with AMD progression. Mixed-effects models for the period between standing and 10 seconds post-stand revealed significant associations with AMD progression with a steeper drop in dBP and a slower drop in TPR. Between 10 and 20 seconds post-stand, AMD progression was significantly associated with less pronounced reduction in heart rate. Conclusions: These observational data suggest that impaired hemodynamic responses within the first 20 seconds of orthostasis may be associated with the progression of AMD.
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Envejecimiento , Presión Sanguínea , Progresión de la Enfermedad , Frecuencia Cardíaca , Degeneración Macular , Humanos , Masculino , Femenino , Anciano , Degeneración Macular/fisiopatología , Irlanda/epidemiología , Frecuencia Cardíaca/fisiología , Envejecimiento/fisiología , Presión Sanguínea/fisiología , Estudios Longitudinales , Sistema Nervioso Autónomo/fisiopatología , Anciano de 80 o más Años , Hemodinámica/fisiología , Persona de Mediana Edad , Factores de RiesgoRESUMEN
OBJECTIVES: This study investigates the mediating roles of autonomic function and mental health in the association between sleep and cognitive decline in adults aged 50 and above. METHOD: A total of 2,697 participants with observations on sleep and mediators at baseline and repeated measures of cognitive function (MMSE) were included. Clusters of individuals with similar cognitive trajectories (high-stable, mid-stable and low-declining) were identified. Multinomial logistic regressions were used to estimate the likelihood of membership to each trajectory group based on sleep duration and disturbance. Finally, mediation analysis tested potential mediating effects of autonomic function and mental health underpinning the sleep-cognition relationship. RESULTS: Short (p = .028), long (p =.019), and disturbed sleep (p =.008) increased the likelihood of a low-declining cognitive trajectory. Mental health measures fully attenuated relationships between cognitive decline and short or disturbed sleep but not long sleep. No autonomic function mediation was observed. CONCLUSION: Older adults with short or disturbed sleep are at risk of cognitive decline due to poor mental health. Individuals with long sleep are also at risk, however, the acting pathways remain to be identified. These outcomes have clinical implications, potentially identifying intervention strategies targeting mental health and sleep as prophylactic measures against dementia.
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Branching morphogenesis is a complex process shared by many organs including the lungs, kidney, prostate, as well as several exocrine organs including the salivary, mammary and lacrimal glands. This critical developmental program ensures the expansion of an organ's surface area thereby maximizing processes of cellular secretion or absorption. It is guided by reciprocal signaling from the epithelial and mesenchymal cells. While signaling pathways driving salivary gland branching morphogenesis have been relatively well-studied, our understanding of the underlying transcriptional regulatory mechanisms directing this program, is limited. Here, we performed in vivo and ex vivo studies of the embryonic mouse submandibular gland to determine the function of the transcription factor ΔNp63, in directing branching morphogenesis. Our studies show that loss of ΔNp63 results in alterations in the differentiation program of the ductal cells which is accompanied by a dramatic reduction in branching morphogenesis that is mediated by dysregulation of WNT signaling. We show that ΔNp63 modulates WNT signaling to promote branching morphogenesis by directly regulating Sfrp1 expression. Collectively, our findings have revealed a novel role for ΔNp63 in the regulation of this critical process and offers a better understanding of the transcriptional networks involved in branching morphogenesis.
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Regulación del Desarrollo de la Expresión Génica , Proteínas de la Membrana , Glándulas Salivales , Animales , Ratones , Diferenciación Celular , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Péptidos y Proteínas de Señalización Intercelular/genética , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Morfogénesis , Glándulas Salivales/metabolismo , Glándulas Salivales/embriología , Glándula Submandibular/metabolismo , Glándula Submandibular/embriología , Transactivadores/metabolismo , Transactivadores/genética , Vía de Señalización WntRESUMEN
Recent research has indicated that the relationship between age-related cognitive decline and falling may be mediated by the individual's capacity to quickly cancel or inhibit a motor response. This longitudinal investigation demonstrates that higher white matter fibre density in the motor inhibition network paired with low physical activity was associated with falling in elderly participants. We measured the density of white matter fibre tracts connecting key nodes in the inhibitory control network in a large sample (n = 414) of older adults. We modelled their self-reported frequency of falling over a 4-year period with white matter fibre density in pathways corresponding to the direct and hyperdirect cortical-subcortical loops implicated in the inhibitory control network. Only connectivity between right inferior frontal gyrus and right subthalamic nucleus was associated with falling as measured cross-sectionally. The connectivity was not, however, predictive of future falling when measured 2 and 4 years later. Higher white matter fibre density was associated with falling, but only in combination with low levels of physical activity. No such relationship existed for selected control brain regions that are not implicated in the inhibitory control network. Albeit statistically robust, the direction of this effect was counterintuitive (more dense connectivity associated with falling) and warrants further longitudinal investigation into whether white matter fibre density changes over time in a manner correlated with falling, and mediated by physical activity.
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Sustancia Blanca , Humanos , Sustancia Blanca/diagnóstico por imagen , Anciano , Masculino , Femenino , Accidentes por Caídas , Encéfalo , Anciano de 80 o más Años , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/fisiología , Estudios Longitudinales , Inhibición PsicológicaRESUMEN
BACKGROUND: Norovirus (NoV) can cause chronic relapsing and remitting diarrhea in immunocompromised patients.⯠Few multicenter studies have described the clinical course, outcomes, and complications of chronic NoV in transplant recipients. METHODS: A multicenter retrospective study of adult and pediatric SOT and HSCT recipients diagnosed with NoV between November 1, 2017, and February 28, 2021. Data were obtained from electronic medical records (EMR) and entered into a central REDCap database. Descriptive statistics were calculated. RESULTS: A total of 280 NoV+ patients were identified across eight sites. The majority were adults (74.1%) and SOT recipients (91.4%). Initial diagnosis of NoV occurred a median of 36 months post-Tx (IQR [15.0, 90.0]). Most NoV cases had >3 diarrheal episodes daily (66.0%), nausea and vomiting (60.1%). Duration of diarrhea varied greatly (median = 10 days, mean = 85.9 days, range (1, 2100)). 71.3% were hospitalized. Adjustment of immunosuppression, including reduction and discontinuation of mToR inhibitor, CNI, and/or MMF, was the most common management intervention for NoV. Other therapies resulted only in temporary improvement. Four patients died within 30 days and three others died by 180 days postdiagnosis. Clinically significant renal dysfunction was observed in 12.5% by 30 days and 21.4% by 180 days post-NoV diagnosis. CONCLUSION: In HSCT and SOT patients, NoV frequently resulted in severe symptoms, prolonged diarrhea (30% persistent with diarrhea for >30 days), and clinically significant renal dysfunction (up to 21% of patients). Utilized therapies did not reliably result in the resolution of infection demonstrating the need for more effective treatment.
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Infecciones por Caliciviridae , Diarrea , Trasplante de Células Madre Hematopoyéticas , Huésped Inmunocomprometido , Norovirus , Trasplante de Órganos , Humanos , Estudios Retrospectivos , Infecciones por Caliciviridae/virología , Masculino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Femenino , Adulto , Niño , Diarrea/virología , Trasplante de Órganos/efectos adversos , Persona de Mediana Edad , Adolescente , Receptores de Trasplantes/estadística & datos numéricos , Preescolar , Adulto Joven , Anciano , Inmunosupresores/uso terapéutico , Inmunosupresores/efectos adversos , Gastroenteritis/virología , LactanteRESUMEN
BACKGROUND: Aimed to compare the prevalence, characteristics, and associated mortality risk of frailty in Northern Ireland (NI) and the Republic of Ireland (ROI). METHODS: Secondary analysis of the first wave of two nationally representative cohorts, the Northern Ireland Cohort for the Longitudinal Study of Ageing or NICOLA study (N = 8504) and the Irish Longitudinal Study on Ageing or TILDA study (N = 8504). Frailty was assessed using a harmonized accumulation deficits frailty index (FI) containing 30 items. FI scores classified individuals as non-frail (<0.10), pre-frail (0.10-0.24) and frail (≥0.25). Linkage to respective administrative data sources provided mortality information with a follow-up time of 8 years. RESULTS: The prevalence of frailty was considerably higher in NI compared with the ROI (29.0% compared with 15.0%), though pre-frailty was slightly lower (35.8% and 37.3%, respectively). Age, female sex, and lower socio-economic status were consistently associated with a higher likelihood of both pre-frailty and frailty. In the pooled analysis, both frailty and pre-frailty were higher in NI (RR = 2.68, 95% CIs 2.45, 2.94 and RR = 1.30, 95% CIs 1.21, 1.40, respectively). Frailty was associated with an increased mortality risk in both cohorts, even after full adjustment for all other characteristics, being marginally higher in TILDA than in NICOLA (HR = 2.43, 95% CIs 2.03, 2.91 vs. HR = 2.31, 95% CIs 1.90, 2.79). CONCLUSIONS: Frailty is a major public health concern for both jurisdictions. Further research and monitoring are required to elucidate why there is a higher prevalence in NI and to identify factors in early life that may be driving these differences.
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Fragilidad , Humanos , Femenino , Masculino , Anciano , Irlanda/epidemiología , Estudios Longitudinales , Fragilidad/epidemiología , Prevalencia , Irlanda del Norte/epidemiología , Anciano de 80 o más Años , Persona de Mediana Edad , Anciano Frágil/estadística & datos numéricos , Evaluación Geriátrica/estadística & datos numéricos , Evaluación Geriátrica/métodos , Factores de RiesgoRESUMEN
Background: Impaired recovery of blood pressure (BP) in response to standing up is a prevalent condition in older individuals. We evaluated the relationship between the early recovery of hemodynamic responses to standing and brain health in adults over 50. Methods: Participants from The Irish Longitudinal Study on Ageing (TILDA) (n=411; age 67.6 ± 7.3 years; 53.4 % women) performed an active stand challenge while blood pressure and heart rate were continuously monitored. The recovery of these parameters was determined as the slope of the BP and HR response, following the initial drop/rise after standing. We have previously reported a novel and validated measure of brain ageing using MRI data, which measures the difference between biological brain age and chronological age, providing a brain-predicted age difference (brainPAD) score. Results: Slower recovery of systolic and diastolic BP was found to be significantly associated with higher brainPAD scores (i.e., biologically older brains), where a one-year increase in brainPAD was associated with a decrease of 0.02 mmHg/s and 0.01 mmHg/s in systolic and diastolic BP recovery, respectively, after standing. Heart rate (HR) recovery was not significantly associated with brainPAD score. Conclusion: These results demonstrate that slower systolic and diastolic BP recovery in the early phase after standing is associated with accelerated brain aging in older individuals. This suggests that the BP response to standing, measured using beat-to-beat monitoring, has the potential to be used as a marker of accelerated brain aging, relying on a simple procedure and devices that are easily accessible.
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BACKGROUND: Although type 2 diabetes mellitus (T2DM) is an established risk factor for cognitive impairment, the underlying mechanisms remain poorly explored. One potential mechanism may be through effects of T2DM on cerebral perfusion. The current study hypothesized that T2DM is associated with altered peripheral and central hemodynamic responses to orthostasis, which may in turn be associated with cognitive impairment in T2DM. METHODS: A novel use of function-on-scalar regression, which allows the entire hemodynamic response curve to be modeled, was employed to assess the association between T2DM and hemodynamic responses to orthostasis. Logistic regression was used to assess the relationship between tissue saturation index (TSI), T2DM, and cognitive impairment. All analyses used cross-sectional data from Wave 3 of The Irish Longitudinal Study on Ageing (TILDA). RESULTS: Of 2 984 older adults (aged 64.3â ±â 8.0; 55% female), 189 (6.3%) had T2DM. T2DM was associated with many features that are indicative of autonomic dysfunction including a blunted peak heart rate and lower diastolic blood pressure. T2DM was associated with reduced TSI and also with greater odds of impaired performance on the Montreal Cognitive Assessment (odds ratio [OR]: 1.62; confidence interval [CI: 1.07, 2.56]; pâ =â .019). Greater TSI was associated with lower odds of impaired performance (OR: 0.90, CI [0.81-0.99]; pâ =â .047). CONCLUSIONS: T2DM was associated with impaired peripheral and cerebral hemodynamic responses to active stand. Both T2DM and reduced cerebral perfusion were associated with impaired cognitive performance. Altered cerebral perfusion may represent an important mechanism linking T2DM and adverse brain health outcomes in older adults.
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Disfunción Cognitiva , Diabetes Mellitus Tipo 2 , Humanos , Femenino , Anciano , Masculino , Diabetes Mellitus Tipo 2/complicaciones , Estudios Longitudinales , Mareo , Estudios Transversales , Disfunción Cognitiva/etiología , HemodinámicaRESUMEN
INTRODUCTION: In Canada, Métis people are one of three distinct Indigenous peoples whose rights are recognised and affirmed in Section 35 of the federal Constitution Act, 1982. In line with Métis people having a unique culture, history, language and way of life, a distinctions-based approach is critical to understand the current landscape of Métis-specific health. In this paper, we present a scoping review protocol to describe this research landscape in Canada led by the Métis Nation of Ontario (MNO). METHODS AND ANALYSIS: This scoping review protocol is reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews reporting guidelines and follows Arksey and O'Malley's scoping review methodology. We will search electronic databases (Scopus, MEDLINE, Embase, Web of Science, CINAHL, APA PsycINFO, Anthropology Plus, Bibliography of Indigenous Peoples of North America, Canadian Business and Current Affairs, Indigenous Studies Portal, Informit Indigenous Collection, Collaborative Indigenous Garden, PubMed, ProQuest), grey literature sources and reference lists from selected papers. Two reviewers (HMB and SK) will double-blind screen all titles/abstracts and full-text studies for inclusion. Any health-related study or health report that includes a Métis-specific health, well-being or Métis social determinant of health outcome will be included. Relevant variables will be extracted following an iterative process whereby the data charting will be reviewed and updated. ETHICS AND DISSEMINATION: Findings from this scoping review will be shared back through the MNO's existing community-based communication channels. Traditional academic dissemination will also be pursued. Research ethics board approval is not required, since data are from peer-reviewed publications or publicly shared health reports and knowledge translation products.
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Proyectos de Investigación , Literatura de Revisión como Asunto , Humanos , América del Norte , OntarioRESUMEN
The molecular detection of Toxoplasma gondii DNA is a key tool for the diagnosis of disseminated and congenital toxoplasmosis. This multicentric study from the Molecular Biology Pole of the French National Reference Center for toxoplasmosis aimed to evaluate Toxoplasma gondii Real-TM PCR kit (Sacace). The study compared the analytical and clinical performances of this PCR assay with the reference PCRs used in proficient laboratories. PCR efficiencies varied from 90% to 112%; linearity zone extended over four log units (R2 > 0.99) and limit of detection varied from 0.01 to ≤1 Tg/mL depending on the center. Determined on 173 cryopreserved DNAs from a large range of clinical specimens, clinical sensitivity was 100% [106/106; 95 confidence interval (CI): 96.5%-100%] and specificity was 100% (67/67; 95 CI: 94.6%-100%). The study revealed two potential limitations of the Sacace PCR assay: the first was the inconsistency of the internal control (IC) when added to the PCR mixture. This point was not found under routine conditions when the IC was added during the extraction step. The second is a lack of practicality, as the mixture is distributed over several vials, requiring numerous pipetting operations. Overall, this study provides useful information for the molecular diagnosis of toxoplasmosis; the analytical and clinical performances of the Sacace PCR kit were satisfactory, the kit having sensitivity and specificity similar to those of expert center methods and being able to detect low parasite loads, at levels where multiplicative analysis gives inconsistently positive results. Finally, the study recommends multiplicative analysis in particular for amniotic fluids, aqueous humor, and other single specimens.
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Toxoplasma , Toxoplasmosis Congénita , Toxoplasmosis , Humanos , Toxoplasma/genética , Toxoplasmosis/diagnóstico , Toxoplasmosis/parasitología , Toxoplasmosis Congénita/diagnóstico , Toxoplasmosis Congénita/parasitología , ADN , Juego de Reactivos para Diagnóstico , Sensibilidad y Especificidad , ADN Protozoario/genética , ADN Protozoario/análisisRESUMEN
Hernández et al. (2019) previously reported independent age and sex differences in temporal audio-visual integration in a large national cohort of older adults. Susceptibility to the sound induced flash illusion (SIFI) at long stimulus onset asynchronies (SOAs) increased with age and was stronger in older adult females than males. However, it is unclear if this sex difference is stable across age. We reanalyzed the data set used by Hernández et al. (2019) on SIFI performance from 3,479 older adults (Mage = 64.20 years, SD = 7.77, range = 50-93; 56% female) across three age groups (50-64, 65-74, and 75+ years), drawn from The Irish Longitudinal Study on Ageing. For the 70 ms SOA, females were less susceptible to the SIFI than males, irrespective of age. At longer SOAs (150 ms and 230 ms), females aged 50-64 years but not older were more susceptible to the SIFI than age-matched males. These findings extend those of Hernández et al. (2019) by indicating that age and sex can collectively influence the precision of multisensory integration exhibited by older adults. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
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Envejecimiento , Percepción Auditiva , Percepción Visual , Humanos , Masculino , Femenino , Anciano , Persona de Mediana Edad , Percepción Auditiva/fisiología , Percepción Visual/fisiología , Envejecimiento/fisiología , Envejecimiento/psicología , Anciano de 80 o más Años , Factores Sexuales , Factores de Edad , Ilusiones/fisiología , Estudios Longitudinales , Caracteres Sexuales , Estimulación Acústica , Estimulación LuminosaRESUMEN
The ionotropic glutamate delta receptor GluD1, encoded by the GRID1 gene, is involved in synapse formation, function, and plasticity. GluD1 does not bind glutamate, but instead cerebellin and D-serine, which allow the formation of trans-synaptic bridges, and trigger transmembrane signaling. Despite wide expression in the nervous system, pathogenic GRID1 variants have not been characterized in humans so far. We report homozygous missense GRID1 variants in five individuals from two unrelated consanguineous families presenting with intellectual disability and spastic paraplegia, without (p.Thr752Met) or with (p.Arg161His) diagnosis of glaucoma, a threefold phenotypic association whose genetic bases had not been elucidated previously. Molecular modeling and electrophysiological recordings indicated that Arg161His and Thr752Met mutations alter the hinge between GluD1 cerebellin and D-serine binding domains and the function of this latter domain, respectively. Expression, trafficking, physical interaction with metabotropic glutamate receptor mGlu1, and cerebellin binding of GluD1 mutants were not conspicuously altered. Conversely, upon expression in neurons of dissociated or organotypic slice cultures, we found that both GluD1 mutants hampered metabotropic glutamate receptor mGlu1/5 signaling via Ca2+ and the ERK pathway and impaired dendrite morphology and excitatory synapse density. These results show that the clinical phenotypes are distinct entities segregating in the families as an autosomal recessive trait, and caused by pathophysiological effects of GluD1 mutants involving metabotropic glutamate receptor signaling and neuronal connectivity. Our findings unravel the importance of GluD1 receptor signaling in sensory, cognitive and motor functions of the human nervous system.
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Discapacidad Intelectual , Receptores de Glutamato Metabotrópico , Transducción de Señal , Sinapsis , Humanos , Discapacidad Intelectual/genética , Masculino , Sinapsis/metabolismo , Sinapsis/genética , Femenino , Receptores de Glutamato Metabotrópico/genética , Receptores de Glutamato Metabotrópico/metabolismo , Transducción de Señal/genética , Homocigoto , Receptores de Glutamato/genética , Receptores de Glutamato/metabolismo , Receptor del Glutamato Metabotropico 5/metabolismo , Receptor del Glutamato Metabotropico 5/genética , Linaje , Adulto , Paraplejía/genética , Paraplejía/metabolismo , Animales , Niño , Neuronas/metabolismo , Adolescente , Células HEK293 , Mutación/genéticaRESUMEN
Diet can influence cognitive functioning in older adults and is a modifiable risk factor for cognitive decline. However, it is unknown if an association exists between diet and lower-level processes in the brain underpinning cognition, such as multisensory integration. We investigated whether temporal multisensory integration is associated with daily intake of fruit and vegetables (FV) or products high in fat/sugar/salt (FSS) in a large sample (N = 2,693) of older adults (mean age = 64.06 years, SD = 7.60; 56% female) from The Irish Longitudinal Study on Ageing (TILDA). Older adults completed a Food Frequency Questionnaire from which the total number of daily servings of FV and FSS items respectively was calculated. Older adults' susceptibility to the Sound Induced Flash Illusion (SIFI) measured the temporal precision of audio-visual integration, which included three audio-visual Stimulus Onset Asynchronies (SOAs): 70, 150 and 230â ms. Older adults who self-reported a higher daily consumption of FV were less susceptible to the SIFI at the longest versus shortest SOAs (i.e. increased temporal precision) compared to those reporting the lowest daily consumption (p = .013). In contrast, older adults reporting a higher daily consumption of FSS items were more susceptible to the SIFI at the longer versus shortest SOAs (i.e. reduced temporal precision) compared to those reporting the lowest daily consumption (p < .001). The temporal precision of multisensory integration is differentially associated with levels of daily consumption of FV versus products high in FSS, consistent with broader evidence that habitual diet is associated with brain health.
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PURPOSE: Frailty is characterised by decreased physiological reserves and vulnerability to stressors. Although scales, such as the Fried's Frailty Phenotype (FP), Frailty Index (FI), and Clinical Frailty Scale (CFS), are used to identify frailty, the lived experience of frailty remains understudied. METHODS: This cross-sectional observational research involved participants aged 65 years and older from Wave 1 of The Irish Longitudinal Study on Ageing (TILDA). Participants were categorised into four independent groups: three frail groups based on the aforementioned scales and a non-frail group. Quantitative variables, including self-rated health, CASP-19 quality-of-life score, and frequency of social activities, were analysed and described. RESULTS: The study encompassed 1999 participants with an average age of 72 years, of whom 51% were women. FP exclusively identified 1.6% as frail (n = 32), FI 11.7% (n = 233), and CFS 6.8% (n = 135). More than 60% of all those classified as frail reported their health as good, very good, or excellent, with the lowest proportion (64%) being among frail by FI participants. Frail by FI participants exhibited the lowest mean average CASP-19 score, yet it remained relatively high at 39 out of 57 points. Over 77% of all frail individuals engaged in active leisure activities at least once a month. CONCLUSION: This study underscores the need to comprehend frailty holistically beyond its mere identification. It challenges the prevailing belief that frailty inevitably leads to impaired quality of life and limited social engagement. The findings advocate for a reassessment of how both the general public and healthcare professionals perceive frailty.